Diabetes mellitus is a metabolic disorder that occurs in approximately four percent of humans. There are two types of diabetes; the non-insulin-dependent or “maturity onset” form (Type 2) and the insulin-dependent or “juvenile onset” form (Type 1). Clinically, the majority of Type 2 diabetics are obese, with manifestations of clinical symptoms of the disease usually appearing in patients over age 40. In contrast, Type 1 diabetics are usually not over-weight relative to their age and height and typically exhibit rapid onset of the disease at an early age, often before age 30.
One-third of diabetes patients suffer from Type 1 diabetes (Foster et al., Harrison's Principles of Internal Medicine, Chap. 114, pp. 661-678, 10th Ed., McGraw-Hill, New York). Type 1 diabetes is an autoimmune disease wherein a state of hyperglycemia results from the T-cell mediated destruction of insulin-secreting b-cells in the pancreatic Islets of Langerhans (Eisenbarth et al., 1986, New Engl. J. Med. 314: 1360-1368). The disease manifests itself as a series of hormone-induced metabolic abnormalities which eventually lead to serious, long-term and debilitating complications involving several organ systems including the eyes, kidneys, nerves, and blood vessels. Pathologically, the disease is characterized by lesions of the basement membranes, demonstrable under electron microscopy.
Type 1 diabetics characteristically show very low or immeasurable plasma insulin with elevated glucagon. Regardless of what the exact etiology is, most Type 1 patients have circulating antibodies directed against their own pancreatic cells including antibodies to insulin, to the islet of Langerhans cell cytoplasm and to the enzyme glutamic acid decarboxylase. An immune response specifically directed against beta cells (insulin producing cells) leads to Type 1 diabetes.
Current therapeutic regimens for Type 1 diabetes include modifications to the diet to minimize hyperglycemia resulting from the lack of natural insulin, which in turn, is the result of damaged beta cells. Diet is also modified with regard to insulin administration to counter the hypoglycemic effects of the hormone. Whatever the form of treatment, parenteral administration of insulin is required for all Type 1 diabetics, hence the term “insulin-dependent” diabetes.
Because Type 1 diabetes usually manifests itself in adolescents and because the subcutaneous delivery of insulin requires strict self-regimentation, compliance is often a serious problem. For the clinician, it is difficult to precisely regulate the amounts of insulin needed at any given time of the patient's day. Furthermore, it is all but impossible to regulate blood glucose levels in diabetic patients with parenteral insulin to the extent to which blood glucose is regulated in normal individuals.
Thus, in the early stages of treatment of Type 1 diabetes, patients often become either hyperglycemic or hypoglycemic because the exact timing of the insulin injections and levels of insulin needed are not known. As treatment progresses the clinician and, more importantly, the patient adjusts to the daily routine, but there is always the risk of ketoacidosis or hypoglycemia.
The pathogenesis of Type 1 diabetes is not fully understood, although various animal models are available for its study. These include the BB mouse (Nakbookda et al., 1978, Diabetologic 14: 199-207,) and the NOD (non-obese diabetic) mouse in which diabetes develops spontaneously (Prochazka et al., 1987, Science 237:286). These mice, especially females, are genetically susceptible to diabetes. Similar to the human condition, the NOD mouse exhibits hyperglycemia, polyuria, polydipsia, glucosuria, insulitis and a dependence on exogenous insulin to sustain life (Tochino et al., 1987, Crit. Rev. Immunol. 8:49-81). Such characteristics have made the NOD mouse an excellent and widely accepted murine model of human Type 1 diabetes.
Vitamin D is a known and potent regulator of calcium and phosphorous metabolism. The biologically active form of Vitamin D, 1α,25-dihydroxyvitamin D3, and its analog in ergocalciferol series, 1α,25-dihydroxyvitamin D2, are highly effective regulators of calcium homeostasis in animals and humans (Ostrem et al., 1987, Proc. Natl. Acad. Sci. USA 84:2610). Many structural analogs of these metabolites have been prepared and tested including 1α-hydroxyvitamin D3 and 1α-hydroxyvitamin D2, each having various homologated side chains and fluorinated analogs thereof. Some compounds exhibited separated cell differentiation and calcium regulation activity. The physiology and molecular actions of vitamin D and its various analogs and metabolites are discussed in Jones et al., 1998, Physiol. Rev. 78:1193-1231 and DeLuca, 2004, Am J Clin Nutr 80 (suppl):16895-16965, which are hereby incorporated herein by reference.
Another class of vitamin D analogs, 19-nor-vitamin D compounds, are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19) by two hydrogen atoms. Biological testing of the 19-nor-analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) demonstrated a selective activity profile having high potency for inducing cellular differentiation as well as very low calcium mobilizing activity. Two synthetic methods have been reported (Perlman et al., 1990, Tetrahedron Lett. 31:1823; Perlman et al., 1991, Tetrahedron Lett. 32:7663, and DeLuca et al., U.S. Pat. No. 5,086,191).
U.S. Pat. No. 4,666,634 to Miyamoto et al. describes 2β-hydroxy and alkoxy analogs of 1α,25-dihydroxyvitamin D3 as potential drugs for osteoporosis and as antitumor agents. (See also Okano et al., 1989, Biochem. Biophys. Res. Commun. 163:1444). Other 2-substituted hydroxyalkyl and fluoroalkyl groups A-ring analogs of 1α,25-dihydroxyvitamin D3 have also been reported (Miyamoto et al., 1993, Chem. Pharm. Bull. 41:1111; Nishii et al., 1993, Osteoporosis Int. Suppl. 1:190; Posner et al., 1994, J. Org. Chem. 59:7855 and Posner et al., 1995, J. Org. Chem. 60:4617).
2-substituted analogs of 1α,25-dihydroxy-19-nor-vitamin D3 have also been synthesized and reported, which are compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713). Binding sites in vitamin D receptors can accommodate different substituents at C-2 in these 19-nor vitamin D analogs.